Compositions for the treatment of migraine, containing potassium, magnesium and pyridoxine

ABSTRACT

Compositions for the treatment and prevention of migraine or stress headaches wherein there is supplied a combination of potassium, magnesium and pyridoxine optionally in association with other nutrients and/or simple analgesics.

This application is a 371 of PCT/GB97/00213, filed on Jan. 24, 1997.

FIELD OF INVENTION

This invention relates to novel treatments for migraine which theinventor believes is triggered by a stress reaction.

BACKGROUND

At the onset of the stress reaction the pituitary gland (triggered bythe hypothalamus) initiates protective action by secreting theadrenocorticotropic hormone ACTH.

This hormone is transported in the blood to the adrenal glands, whichimmediately respond to deal with this stress emergency signal, byproducing cortisol and aldosterone.

Under non-stress conditions the adrenal glands utilise certain vitaminsand minerals in order to function. In order to respond to stress theyneed an increased supply of vitamins and minerals. These additionalsupplies are rapidly used up in the stress response reaction. Thereforethe adrenal glands ability to resist stress is dependent upon the supplyof these "activator" nutrients. If stress is prolonged, or chronic,ultimately the adrenal glands will exhaust themselves through the lackof readily available activator nutrients. Some nutrients areparticularly susceptible to depletion.

Vitamin B₆ (pyridoxine) is needed by the adrenals and in proteinsynthesis and in manufacture of vitamin B₃. If used in quantity tomanufacture B₃ to counteract stress, less is available to the adrenalsor for protein synthesis. Additional supplies of vitamin B₆ are "stolen"from any available sources to answer stress demands. As another part ofthe stress response mechanism, intracellular potassium, lost from thebody in the urine in response to aldosterone, is replaced by potassiumheld in store within the muscle tissues and bones. There is an overallpotassium depletion. Cortisol, produced with aldosterone during thestress reaction, requires a range of nutrients to exert its effects, butparticularly vitamin B₆ and potassium. Histamine may be produced as aconsequence of the stress response. Histamine production can be one ofthe features of a migraine attack.

As a result of sustained stress, the blood sugar level rises markedly tomeet the immediate need but then may drop significantly as a conditionof adrenal exhaustion is precipitated. At this point cortisol ceases torapidly stimulate conversion of protein into sugar and cannot keep pacewith the stress induced sugar demands. This may result in hypoglycaemiawhich also may be a feature of migraine attacks.

As a further stress response, aldosterone is also secreted by theadrenal glands in abnormally large amounts. This immediately triggersthe kidneys to retain salt and water while losing potassium.

Consequences of this process may be an elevation of the blood pressureand the expulsion of intracellular potassium. This loss of potassiumfrom cells may cause many adverse consequences since all tissues of thebody, especially muscles and nerves, require a normal cellular potassiumbalance. The sodium retention and potassium loss may cause elevation ofblood pressure and acidosis which also can be features of a migraineattack. The potassium loss may be particularly important.

The body relies upon vitamins and minerals for the efficient functioningof the nervous system. Many act in a synergistic mode and cannotfunction fully without the help of other contributory elements. A lackof one affects all.

A number of vitamins and minerals play multiple roles in the stressresponse and act in concert to deal with stress. For example, vitamin B₅and vitamin C which may be used to help counteract stress, are alsoprime activators of the adrenal glands. Vitamin B₆ is vital for thenervous system, and essential to the adrenal glands. The B vitamins aresynergistic and all may need to be given in order to be fullyfunctional. Vitamin C requires bioflavonoids for optimum efficiency.

Furthermore, in order to exert many of its functions, vitamin B₆requires the presence of the mineral magnesium. Magnesium is alsoessential to normal adrenal gland function. Magnesium can be ananti-stress nutrient, capable of reducing aldosterone production,thereby preventing the kidneys from retaining salt and water andcontinuing to drive out potassium.

Migraine is a reaction to stress which occurs in some people and whichcan be triggered in all stages of the stress response cycle. Many of thebiochemical conditions which are induced by stress may cause certainsymptoms which are considered to be intrinsic to a migraine attack. Thestress and migraine responses appear to progress in a similar way.

Migraine attacks may be the results of stresses upon the body. Thestress can be emotional, hormonal, an allergic reaction (including foodallergy), poisoning from toxic substances such as tobacco and alcohol,paint fumes and chemical gases (e.g. combustion engine exhaustemissions, gas and coal burning boiler fumes), a response to irregularmeals or exercise, or a response to changes in the weather. Temperaturesensitivity can also trigger migraine. In some cases, the stress isphysical, resulting from physical abnormalities in the body's muscularor skeletal structure, often caused by accident or injury or excessiveuse.

In a migraine attack, most but not all sufferers first experience earlywarning symptoms which signal the commencement of a full blown migraineattack. All the senses are affected, but all sufferers do not experienceall forms of sensory deviation. This phase is thought to occur as theblood supply to the brain is restricted. There is sometimes a reductionin urine flow.

Vision

A very common phenomenon is the visual corona which registers upon theretina, often taking the form of a sparkling coloured zigzag "halo"which distorts the vision. Another visual signal can be patches ofdistortion within the field of vision (somewhat akin to looking througha rain spattered pane of glass). Some people develop acute sensitivityto light, or other less common visual symptoms.

Taste

Some sufferers experience a "sweet taste" upon their palate when nosugar is present, or some other taste distortion.

Hearing

Some sufferers experience tinnitus (ringing of the ears) or a certainloss of sound definition. Sometimes there is acute sensitivity to sound.

Touch

Some experience"tingling" sensations often in the face and extremities,some lose feeling altogether (parasthesia--temporary paralysis).

Other Symptoms

Dizziness, loss of balance, nausea, vomiting, sugar craving, stomachpain, sudden fatigue or sudden irritability with no apparent cause, arealso premonition symptoms.

Whatever form of early warning occurs, there follows a second stage ofthe attach. It may follow on immediately or after a hiatus period whenno symptoms of any kind are experienced until the second stagecommences. This "rest period" usually lasts from 10 minutes up to anhour but can last up to 24 hours.

Once the attack enters the second stage, all of the early warningsymptoms can develop further, almost always accompanied by extreme headpain. Some people have to lie in a darkened room, excluding all lightand any movement to quell pain and vomiting.

This second stage can have a duration of a few hours or several days.

While the sensory disorientation experienced by migraine sufferersappears to be a direct effect of impaired blood supply to the relevantreceptors within the brain, other migraine symptoms correlate with thestages of stress response. I therefore conclude that the migraine cycleand the stress response are closely related.

One medical response to migraine is to attempt to eliminate the cause ofmigraine (if this is known). This is most easily ascertained if thecause is a definite food allergy such as cheese, wine or chocolate butthis approach is not often successful.

If elimination proves unsuccessful then the only medical alternative ispain control or drug therapy to try to block the occurrence of migraineby drugs which act on neurotransmitters associated with stress such asserotonin and catecholamines or by analgesics. The pain of migraine isvery difficult to eradicate. The strongest drugs commonly prescribed formigraine have to be given at near toxic levels to be at all efficacious.Most drugs, administered in "safe" doses are unable to completelyrelieve head pain. Even with the best of modern therapy many patientsobtain only partial relief from their attacks.

The Invention

The invention is set out in the claims herein but simply stated theinventor has devised a method of treating migraine which involves thesupply of three key ingredients, potassium, magnesium and pyridoxine.These three ingredients are effective alone but optionally may becombined with other nutrients and/or simple analgesics. Whether or notthe theory on which the formulation is based is correct, the inventorhas found this approach to be effective in treating migraine.

the present invention thus in one aspect provides a composition for usein combating by preventing or treating the effects of migraine, saidcomposition comprising potassium, Vitamin B₆ and magnesium, as essentialingredients. Optionally these three essentials may be combined withother nutrients and/or simple analgesics.

The term "composition" is used herein to include separate formulationswhich are intended for co-administration, either sequentially orsimultaneously. It is generally more convenient however for thecomposition to be in a single admixture formulation.

In one embodiment, the composition comprises the active ingredients inamounts as follows, provided in the form of any appropriate salt orother derivative as well known to those skilled in the art:

    ______________________________________                                        Potassium    10 mg to 5000 mg, preferably 100 mg to                                        1000 mg and very preferably 300 mg to                                         600 mg.                                                          Vitamin B.sub.6                                                                            0.1 to 200 mg, preferably 1 mg to 100                                         mg and very preferably from 4 mg or 5                                         mg up to 30 mg.                                                  and                                                                           Magnesium    1.0 to 1000 mg, preferably 10 mg to 500                                       mg, very preferably 20 mg to 300 mg.                             ______________________________________                                    

The composition may provide the three primary active ingredients aloneor may provide these three together with other minerals and vitaminsimportant in the stress response including calcium, phosphorus, iron,iodine and the water soluble vitamins vitamin B₁, vitamin B₂, vitaminB₃, vitamin B₅, vitamin B₁₂, folic acid, biotin, bioflavonoids andvitamin C. Optionally said composition may further comprisetherapeutically effective amounts of copper, manganese and/or zinc.Tryptophan, which is a precursor of serotonin, which may be depleted ina migraine attack may also be included, preferably without other aminoacids.

The formulation preferably does not contain any fats or fat solublevitamins and it omits carbohydrates other than excipients andsweeteners; it is certainly not in any sense nutritionally complete andis thus not intended as a supplement for nutritional purposes.

Simple analgesics which may be included in the formulation includesaspirin (10-2000 mg), paracetamol (acetaminophen) (10-2000 mg),ibuprofen (10-2000 mg) or any non-steroidal anti-inflammatory drug.

The compositions according to the invention may be administered in anyconvenient form known to those skilled in the art. These forms includecapsules of various types, powders, effervescent formulations, tablets,solutions, suspensions, emulsions and also aerosol sprays. Thecompositions may be administered orally, enterally, parenterally ortransdermally using appropriate technology known to those skilled in theart.

In a further aspect, the present invention provides the use of a vitaminand mineral combination, or the use of any one or two of the componentsof the combination when for co-administration with the other(s) whethersequentially or simultaneously, in the manufacture of a medicament tocombat migraine, said combination comprising therapeutically effectiveamounts of potassium, vitamin B₆ and magnesium. Further ingredients maybe optionally included as described above, for example the compositionmay include an analgesic.

In a yet further aspect, the present invention provides a method ofcombating migraine, in a person subject to the same, said methodcomprising administering to said person a composition as describedabove, the components being given sequentially or simultaneously.

The active ingredients of the composition may be present in combinationwith any pharmaceutically acceptable carrier and may be in anyassimilable form as well known to those skilled in the art for anyparticular ingredient. One possible carrier is water and in a preferredembodiment the composition is in the form of a tablet which effervesceswhen placed into water to produce aqueous solution which is thenswallowed by the patient. Emulsions and flavoured solutions orsuspensions are also possible formulations.

This formula has been tested in volunteer migraine sufferers. When theformula is taken as soon as any premonition symptoms are experienced,many sufferers do not develop the full scale migraine attack they areexpecting.

These studies also have demonstrated that the formula, even when itcontains no analgesics whatsoever, has a beneficial effect, even iftaken after the stage of migraine pain is reached. In some cases, itremoved all symptoms, with the exception of a "mild" headache, orgreatly reduced the expected severity. For others it completely clearedall symptoms.

The study to date has demonstrated that 70% of the volunteersexperienced full relief from debilitating migraine symptoms. A further20% experienced partial relief, i.e. a reduction of all symptoms exceptfor a mild headache, and for 10% the remedy appeared to have no effect.A number of the volunteers in the 20% partial success category appear tosuffer from migraine in the form in which it has few if any premonitionsymptoms. As a result they were unable to determine when an attach wasimminent and could not take the remedy at the optimum time, i.e. beforehead pain commenced. for those who experience this type of attack,called "common migraine", it is considered that the addition of a simpleanalgesic would be particularly beneficial.

EXAMPLES

There follow examples of formulas incorporating the invention, theparticular form of the actives being merely for illustration. Anyappropriate form as well known to those skilled in the art may be used.All figures are in mg and represent a unit dosage form which should betaken as early as possible during an attack. If relief is not obtainedwithin 2 hours, a second dose may be taken, and further doses may betaken later.

    ______________________________________                                                     1    2      3      4    5    6                                   ______________________________________                                        Potassium (e.g. as chloride or                                                               400    450    350  600  470.0                                                                              470.0                             sulphate)                                                                     Magnesium (e.g. as citrate)                                                                  20     30     30   40   2.5  10                                Pyridoxine     20     20     15   30   5    10                                Calcium (e.g. as citrate)                                                                    --      --    --   --   25.0 60.0                              Phosphorus (e.g. as dicalcium                                                                --     --     --   --   22.5 27.0                              phosphate)                                                                    Iron (e.g. as sulphate)                                                                      --     --     --   --   0.625                                                                              0.1                               Copper (e.g. as sulphate)                                                                    --     --     --   --   0.05 0.5                               Zinc (e.g. as citrate)                                                                       --     --     --   --   0.25 0.001                             Manganese (e.g. as gluconate)                                                                --     --     --   --   0.25 --                                Iodine (e.g. as potassium                                                                    --     --     --   --   --   0.15                              iodide)                                                                       ______________________________________                                    

To the formula may also be added other vitamins or nutrients such as thefollowing (all figures are in mg):

    ______________________________________                                        Vitamin B.sub.1  7.5     5.0                                                  Vitamin B.sub.2  2.5     5.0                                                  Vitamin B.sub.3  25.0    25.0                                                 Vitamin B.sub.5  5.0     10.0                                                 Vitamin B.sub.12 0.0025  0.035                                                Tryptophan       100     500                                                  Folic Acid       0.15    0.2                                                  Biotin           0.125   0.002                                                Vitamin C        75.0    60.0                                                 Bioflavonoids    5.0     10.0                                                 ______________________________________                                    

To any of the formulae illustrated above, analgesics may be added suchas 1000 mg of aspirin or 1000 mg of ibuprofen or 800 mg of paracetamol.The minerals, vitamins and analgesic may all be presented together or asdifferent components within the same overall package.

As noted above the compositions of the invention are not full dietarysupplements or nutritionally complete and the composition claims belowdo not extend when analgesics are absent to the many published instancesof such, comprising besides the minerals and vitamins of the inventionmany other components and in particular fats, fatty acids and/or fatsoluble vitamins.

A specific example is the following two-part formulation, one tablet ofeach kind:

a) Effervescent Mineral Tablet

    ______________________________________                                        Potassium chloride     600 mg                                                 Potassium bicarbonate  400 mg                                                 Anhydrous citric acid  800 mg                                                 ______________________________________                                    

providing: 470 mg potassium; 285 mg chloride; 787.5 mg citrate

This was tested successfully at full strength and half strength (fullstrength listed above). A small proportion of sodium salts was present(sodium 2.6 mg).

b) Multi-vitamin Tablet

Magnesium sulphate

Pyridoxine hydrochloride

Phosphorus as dicalcium phosphate

Iron sulphate

Copper sulphate

Zinc sulphate

Manganese sulphate

Iodine as potassium iodide

B₁ Thiamine mononitrate

B₂ Riboflavin

B₃ Nicotinamide

B₅ pantothenic acid

B₁₂ cyanocobalamin

Tryptophan

Folic acid

Biotin

Vitamin C as ascorbic acid

Bioflavonoids

The multi-vitamin tablets give the recommended daily intake ofcomponents having such recommendation, and in particular 8 mg magnesiumand 7.5 mg pyridoxine. Rapid uptake of the potassium was aided by theeffervescence of the mineral tablets.

What is claimed is:
 1. A method of treating migraine headaches byadministering, separately or simultaneously, to a patient subject tomigraine headaches 10 to 5000 mg of assimilable potassium, 0.1 to 300 mgpyridoxine and 1 to 1000 mg assimilable magnesium.
 2. A method fortreating migraine, according to claim 1, by administering saidpotassium, pyridoxine and magnesium at an early warning stage of amigraine attack.
 3. The method of treating migraine according to claim 1wherein effective amounts of additional minerals and vitamins selectedfrom the group consisting of calcium, phosphorus, iron, copper, zinc,manganese, tryptophan, folic acid, biotin, bioflavonoids and vitaminsB₁, B₂, B₃, B₅, B₁₂ and C are administered to said patient.
 4. Themethod of treating migraine according to claim 1 wherein an effectivedose of an analgesic or non-steroidal anti-inflammatory drug is alsoadministered to said patient.
 5. The method of treating migraineaccording to claim 1, wherein the administration of said amounts ofassimilable potassium, pyridoxine and assimilable magnesium to saidpatient is repeated at two-hourly intervals until effective relief frommigraine symptoms is obtained.
 6. The method of treating migraineaccording to claim 1, wherein said assimilable potassium is administeredby means of an effervescent mineral tablet containing potassiumchloride, potassium bicarbonate and anhydrous citric acid; saidpyridoxine and assimilable magnesium being separately administered bymeans of a multi-vitamin tablet containing magnesium sulphate,pyridoxine hydrochloride, dicalcium phosphate, iron sulphate, coppersulphate, zinc sulphate, manganese sulphate, potassium iodide, thiaminemononitrate, riboflavin, nicotinamide, pantothenic acid, cyanocobalamin,tryptophan, folic acid, biotin, ascorbic acid and bioflavonoids.
 7. Themethod of treating migraine according to claim 3, wherein the amounts ofsaid additional minerals and vitamins are in the following ranges:

    ______________________________________                                        Vitamin B.sub.1     5.0-7.5 mg                                                Vitamin B.sub.2     2.5-5.0 mg                                                Vitamin B.sub.3     25.0 mg                                                   Vitamin B.sub.5     5.0-10.0 mg                                               Vitamin B.sub.12    0.0025-0.035 mg                                           Tryptophan          100-500 mg                                                Folic Acid          0.15-0.2 mg                                               Biotin              0.002-0.125 mg                                            Vitamin C           60.0-75.0 mg                                              Bioflavonoids       5.0-10.0 mg                                               ______________________________________                                    


8. The method of treating migraine according to claim 4 wherein saidanalgesic dose consists of 1000 mg aspirin.
 9. The method of treatingmigraine according to claim 4 wherein said analgesic dose consists of1000 mg ibuprofen.
 10. The method of treating migraine according toclaim 4 wherein said analgesic dose consists of 800 mg paracetamol. 11.A method of treating migraine headaches by administering, separately orsimultaneously, to a patient subject to migraine headaches, 100 mg to1000 mg of assimilable potassium, 1 mg to 100 mg pyridoxine and 10 mg to500 mg assimilable magnesium.
 12. A method of treating migraineheadaches by administering, separately or simultaneously, to a patientsubject to migraine headaches, 300 mg to 600 mg of assimilablepotassium, 4 mg to 30 mg pyridoxine and 20 mg to 300 mg assimilablemagnesium.